DESCRIPTION Hip fracture is a catalyst for profound morbidity and mortality. Despite high bone mineral density (BMD), persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture compared to those without diabetes. Conventionally, high BMD predicts favorable skeletal strength. BMD alone is an inadequate predictor of fracture risk in T2DM. The pathophysiology underlying the discordance between BMD and fracture risk in T2DM is unknown. Bone strength and fracture risk depend on 1) bone quantity, defined by BMD, and mailto:lixiang@csr.nih.gov2) bone quality, defined by skeletal parameters including bone geometry, microarchitecture, mineralization and remodeling. The central hypothesis is that during the transition from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to overt T2DM, bone quality deteriorates despite maintenance of bone quantity. This leads to increased fracture risk. The long-term goal of this research is to identify how the biochemical and metabolic derangements characteristic of glucose intolerance are deleterious to bone. The objective of this proposal is to investigate differences in bone quantity and quality across the three categories of glucose homeostasis, specifically normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2DM. Parameters of bone quality have not been examined in persons with IGT and T2DM. The central hypothesis will be tested by pursuing three specific aims: 1) To compare differences in skeletal quantity and bone geometry in NGT, IGT and T2DM. Dual x-ray absorptiometry and quantitative computed-tomography (CT) performed on men and women in the Baltimore Longitudinal Study of Aging across the three categories of glycemic control will be used to compare areal BMD, volumetric BMD and hip geometry from hip structure analysis. 2) To evaluate differences in skeletal quantity and bone microarchitecture & mineralization in NGT, IGT and T2DM. Tetracycline-labeled transiliac bone biopsies will be performed in recruited postmenopausal women in the three categories of glucose homeostasis. Micro-CT and histomorphometry of bone biopsy samples will be evaluated. 3) To analyze differences in parameters of active bone remodeling in NGT, IGT and T2DM. Markers of bone formation and resorption will be measured in the sera of recruited postmenopausal women. Osteoclast and osteoblast number and co-localization will be measured by immunostaining for osteogenic markers in the bone biopsies of recruited subjects. This approach is novel because understanding the changes in bone quality that occur with progressive diabetes will provide the basis to: 1) Assess when deranged glucose homeostasis alters bone quality and thus increases fracture risk; 2) Determine how to screen those at risk for fracture beyond BMD measurement; 3) Determine when to initiate treatment to prevent fracture in T2DM; 4) Decide which existing therapy will best address the underlying pathology of bone fragility in T2DM; 5) Develop new interventions based on the underlying pathology of the bone fragility observed in T2DM. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because identifying the cause of bone fracture with deteriorating glucose control will speed the discovery of effective strategies for hip fracture prevention and treatment in men and women with diabetes. Fracture is a devastating event with dismal health consequences. Therefore, this research will help prevent future disability and frailty in this at-risk population.